TY - JOUR T1 - Epidermal Growth Factor Receptor Agonists Increase Expression of Glutamate Transporter GLT-1 in Astrocytes through Pathways Dependent on Phosphatidylinositol 3-Kinase and Transcription Factor NF-κB JF - Molecular Pharmacology JO - Mol Pharmacol SP - 667 LP - 678 DO - 10.1124/mol.57.4.667 VL - 57 IS - 4 AU - Olga Zelenaia AU - Brian D. Schlag AU - Gordon E. Gochenauer AU - Raquelli Ganel AU - Wei Song AU - Jacqueline S. Beesley AU - Judith B. Grinspan AU - Jeffrey D. Rothstein AU - Michael B. Robinson Y1 - 2000/04/01 UR - http://molpharm.aspetjournals.org/content/57/4/667.abstract N2 - The glial glutamate transporter GLT-1 may be the predominant Na+-dependent glutamate transporter in forebrain. Expression of GLT-1 correlates with astrocyte maturation in vivo and increases during synaptogenesis. In astrocyte cultures, GLT-1 expression parallels differentiation induced by cAMP analogs or by coculturing with neurons. Molecule(s) secreted by neuronal cultures contribute to this induction of GLT-1, but little is known about the signaling pathways mediating this regulation. In the present study, we determined whether growth factors previously implicated in astrocyte differentiation regulate GLT-1 expression. Of the six growth factors tested, two [epidermal growth factor (EGF) and transforming growth factor-α] induced expression of GLT-1 protein in cultured astrocytes. Induction of GLT-1 protein was accompanied by an increase in mRNA and in the V max for Na+-dependent glutamate transport activity. The effects of dibutyryl-cAMP and EGF were additive but were independently blocked by inhibitors of protein kinase A or protein tyrosine kinases, respectively. The induction of GLT-1 in both EGF- and dibutyryl-cAMP-treated astrocytes was blocked by inhibitors targeting phosphatidylinositol 3-kinase (PI3K) or the nuclear transcription factor-κB. Furthermore, transient transfection of astrocyte cultures with a constitutively active PI3K construct was sufficient to induce expression of GLT-1. These data suggest that independent but converging pathways mediate expression of GLT-1. Although an EGF receptor-specific antagonist did not block the effects of neuron-conditioned medium, the induction of GLT-1 by neuron-conditioned medium was completely abolished by inhibition of PI3K or nuclear factor-κB. EGF also increased expression of GLT-1 in spinal cord organotypic cultures. Together, these data suggest that activation of specific signaling pathways with EGF-like molecules may provide a novel approach for limiting excitotoxic brain injury. ER -